The effect of regulatory T cells in Schistosoma-mediated protection against type 2 diabetes.

In western societies, the prevalence of type 2 diabetes (T2D) is related to the hygiene hypothesis, which implies that reduced exposure to infectious factors results in a loss of the immune stimulation necessary to form the immune system during development. In fact, it has been reported that parasites, such as Schistosoma, can improve or prevent the development of T2D, which may be related to the activity of immune cells, including regulatory T cells (Tregs). Hence, Schistosoma, Tregs, and T2D share a close relationship. Schistosoma infection and the molecules released can lead to an increase in Tregs, which play an important role in the suppression of T2D. In this review, we provide an overview of the role of Tregs in the response to Schistosoma infection and the protective mechanism of Schistosoma-related molecular products against T2D.

Quantitative and noninvasive assessment of prenatal X-ray-induced CNS abnormalities using magnetic resonance imaging.

Our purpose was to noninvasively assess formation of the microvasculature, blood-brain barrier (BBB) and blood-CSF barrier formation of prenatal X-ray-induced CNS abnormalities using quantitative MRI. Eight pregnant female Sprague-Dawley rats were divided into two groups consisting of control and X-irradiated animals. After birth, 20 neonatal male rats were divided into four groups of five rats. To evaluate the development of the BBB, changes in T(1) induced by Gd-DTPA were compared quantitatively in normal and prenatally irradiated animals in the formative period 1 to 2 weeks after birth. To assess the abnormalities of the microvasculature, quantitative perfusion MRI and MR angiography were also used. Histology was also performed to evaluate the BBB (albumin) and vascular endothelial cells (laminin). Decreased cerebral blood flow (CBF) and angioarchitectonic abnormalities were observed in the prenatally irradiated rats. However, abnormalities of the BBB and blood-CSF barrier were not observed using Gd-enhanced MRI and albumin staining. Quantitative perfusion MRI, MR angiography and Gd-enhanced T(1) mapping are useful for assessing CNS disturbance after prenatal exposure to radiation. These techniques provide important diagnostic information for assessing the condition of patients during the early stages of life after accidental or unavoidable prenatal exposure to radiation.

Developments of sulcal pattern and subcortical structures of the forebrain in cynomolgus monkey fetuses: 7-tesla magnetic resonance imaging provides high reproducibility of gross structural changes.

The aim of this study was to spatio-temporally clarify gross structural changes in the forebrain of cynomolgus monkey fetuses using 7-tesla magnetic resonance imaging (MRI). T(1)-weighted coronal, horizontal, and sagittal MR slices of fixed left cerebral hemispheres were obtained from one male fetus at embryonic days (EDs) 70-150. The timetable for fetal sulcation by MRI was in good agreement with that by gross observations, with a lag time of 10-30 days. A difference in detectability of some sulci seemed to be associated with the length, depth, width, and location of the sulci. Furthermore, MRI clarified the embryonic days of the emergence of the callosal (ED 70) and circular (ED 90) sulci, which remained unpredictable under gross observations. Also made visible by the present MRI were subcortical structures of the forebrain such as the caudate nucleus, globus pallidus, putamen, major subdivisions of the thalamus, and hippocampal formation. Their adult-like features were formed by ED 100, corresponding to the onset of a signal enhancement in the gray matter, which reflects neuronal maturation. The results reveal a highly reproducible level of gross structural changes in the forebrain using a high spatial 7-tesla MRI. The present MRI study clarified some changes that are difficult to demonstrate nondestructively using only gross observations, for example, the development of cerebral sulci located on the deep portions of the cortex, as well as cortical and subcortical neuronal maturation.

Spatial learning and expression of neural cell adhesion molecule L1 in rats X-irradiated prenatally.

The present study was designed to present evidence to clarify the relationships between learning ability, neuronal cell adhesion molecule L1 expression and hippocampal structural changes in the rat model received X-irradiation at an embryonic stage (E15). Water maze task indicated that all of the irradiated rats failed to learn the task in the whole training procedure. Their latency to the platform and swimming distance were significant differences from those sham-treated controls. Histological studies showed that the hippocampal ectopias induced by X-rays in the CA1 were involved in the spatial learning impairment, in which they hampered normal processes in learning development and transmission of information. Number, size and positions of the ectopias in the dorsal parts of the hippocampus were confirmed to be related to degrees of spatial learning impairment. On the other hand, L1 expression in the hippocampus was examined with Western blot analysis. The results indicated a lower content of L1 in the irradiated rats. A decrease in L1 might be one of reasons to cause disorganization of the septohippocampal pathways. These findings suggest some mechanisms of spatial learning impairment can be attributed to the formation of the hippocampal ectopias and redaction of L1 following prenatal exposure to X-irradiation.

Abnormal expression of tyrosine hydroxylase not accompanied by phosphorylation at serine 40 in cerebellar Purkinje cells of ataxic mutant mice, rolling mouse Nagoya and dilute-lethal.

This study examined immunohistochemically the expression of an enzymatically active form of tyrosine hydroxylase (TH), phosphorylated TH at Ser40 (phospho-TH), in the cerebellum of ataxic mutant mice, rolling mouse Nagoya (RMN) and dilute-lethal (DL). TH immunostaining appeared in some Purkinje cells in RMN and DL, but in a few of the Purkinje cells of littermate controls for both mutants. In all groups of mice, there were no phospho-TH immunoreactive Purkinje cells in the cerebellum, although the subsets of TH immunoreactive Purkinje cells were found in the adjacent sections. The results suggest that TH expression in the Purkinje cells of ataxic mutants abnormally increases without activation of this enzyme by phosphorylation. This may mean that TH in Purkinje cells is not related to catecholamine synthesis.

Experimental model for irradiating a restricted region of the rat brain using heavy-ion beams.

Heavy-ion beams have the feature to administer a large radiation dose in the vicinity of the endpoint in the beam range, its irradiation system and biophysical characteristics are different from ordinary irradiation instruments like X-rays or gamma-rays. In order to get clarify characteristic effects of heavy-ion beams on the brain, we have developed an experimental system for irradiating a restricted region of the rat brain using heavy-ion beams. The left cerebral hemispheres of the adult rat brain were irradiated at dose of 50 Gy charged carbon particles (290 MeV/nucleon; 5 mm spread-out Bragg peak). After irradiation, the characteristics of the heavy-ion beams and the animal model were studied. Histological examination and measurement showed that extensive necrosis was observed between 2.5 mm and 7.5 mm depth from the surface of the rat head, suggesting a relatively high dose and uniform dose was delivered among designed depths and the spread-out Bragg peak used here successfully and satisfactorily retained its high-dose localization in the defined region. We believe that our experimental model for irradiating a restricted region of the rat brain using heavy-ion beams is a good model for analyzing regional radiation susceptibility of the brain.

Ectopic neurons in the hippocampus may be a cause of learning disability after prenatal exposure to X-rays in rats.

The relationship between an impairment of spatial navigation and an incidence of ectopic neurons in the dorsal hippocampus was investigated in adult rats that were prenatally exposed to X-ray irradiation. Adult rats which had received 1.5 Gy X-rays at embryonic day 15 (E15) showed significant learning disability in the water-maze task. According to the mean value of the swimming time, we categorized the irradiated adult rats into the following three groups: slightly damaged group, mildly damaged group and severely damaged group. No significant difference in the brain weight was found between the three categorized groups. Ectopic neurons appearing at abnormal places were prominently observed in the dorsal hippocampus of the severely damaged group with a remarkable learning disturbance, while no ectopia in the hippocampus was observed in the slightly damaged group. This may suggest that the cognitive dysfunction induced by prenatal exposure to X-ray irradiation may be, at least in part, attributable to ectopic neurons of the hippocampus.

Expression of neural cell adhesion molecule L1 in the brain of rats exposed to X-irradiation in utero.

To gain insight to the cellular and molecular mechanisms involved abnormal neuronal migration induced by irradiation, we investigated expression of neuronal cell adhesion molecule L1 and neuronal migration in the brains through comparison between rats prenatally exposed to X-ray and controls. To observe the pattern of neuronal migration, bromodeoxyuridine (BrdU) was chosen as a marker to label migrating cells. The results showed some of the labeled cells remained in the lower of the cortical plate in the irradiated rats, suggesting that neuronal migration was disrupted by X-ray. To study change of expressing neural cell molecule L1, rat brains were analyzed by SDS-PAGE after isolation of L1 by immunoaffinity chromatography. In the all brain membrane fraction, immunoaffinity purified L1 had bands at 200, 180, 140 and 80 kDa. However, the bands in the irradiated group were very weak when compared with the control. Taking these results into account, abnormal neuronal migration and reduction of expression L1 found in the irradiated brain indicated that migration of neural cells may be largely dependent on radial glial fiber as well as neural cell molecules like L1. A decrease in L1 expression may be one of reasons of abnormal neuronal migration.

A genetic mouse model carrying the nonfunctional xeroderma pigmentosum group G gene.

A genetic mouse model with a disrupted XPG allele was generated by insertion of neo cassette sequences into exon 3 of the XPG gene by using embryonic stem (ES) cell techniques. The xpg-deficient mice showed distinct developmental characteristics. Their body was marked smaller than that in wild-type littermates since the postnatal day 6, and this postnatal growth failure became more severe with developmental proceeding. Their life span was very short, all of the mutants died by postnatal day 23 after showing great weakness and emaciation. In addition, the mutant homozygous mice also showed some progressive neurological signs, like the lower level of activity and a progressive ataxia. Further examination indicated there was developmental retardation of the brain in the mutant mice. Their brain weight, and thickness of cerebral cortex and cerebellar cortex were significant different from the controls. These characteristics, like small size brain, brain developmental retardation and progressive neurological dysfunctions in the homozygotes were similar to the typical clinical phenotype of the XPG patients and Cockayne syndrome, we believe that the xpgdeficient mice will be an animal model for studying the function of the XP-G protein in nucleotide-excision repair and mechanisms related to the clinic symptoms of XP-G and Cockayne syndrome in humans.

Histological and elemental changes in the rat brain after local irradiation with carbon ion beams.

The left cerebral hemispheres of adult Sprague-Dawley rat brains were irradiated at doses of 30, 50, or 100 Gy with charged carbon particles (290 MeV/nucleon; 5 mm spread-out Bragg peak). The spread-out Bragg peak used here successfully and satisfactorily retained its high-dose localization in the defined region. A histological examination showed that necrotic tissue damage, hemorrhage in the thalamus, and vasodilatations around the necrotic region were induced at 8 weeks after 100 Gy irradiation. The regions with tissue damage correlated well with those expected from the radiation-dose distribution, indicating an advantage of charged carbon particles for irradiating restricted brain regions. An X-ray fluorescent analysis demonstrated a decrease in the concentrations of K and P, and an increase in the concentrations of Cl, Fe, Zn in the damaged region at 8 weeks post-irradiation, though no significant changes were observed before 4 weeks of post-irradiation. This may indicate that even the very high radiation doses used here did not induce acute and immediate neuronal cell death, in contrast with ischemic brain injury where acute neuronal cell death occurred and the elemental concentrations changed within a day after the induction of ischemia.

Normal and abnormal neuronal migration in the developing cerebral cortex.

Neuronal migration is the critical cellular process which initiates histogenesis of cerebral cortex. Migration involves a series of complex cell interactions and transformation. After completing their final mitosis, neurons migrate from the ventricular zone into the cortical plate, and then establish neuronal lamina and settle onto the outermost layer, forming an "inside-out" gradient of maturation. This process is guided by radial glial fibers, requires proper receptors, ligands, other unknown extracellular factors, and local signaling to stop neuronal migration. This process is also highly sensitive to various physical, chemical and biological agents as well as to genetic mutations. Any disturbance of the normal process may result in neuronal migration disorder. Such neuronal migration disorder is believed as major cause of both gross brain malformation and more special cerebral structural and functional abnormalities in experimental animals and in humans. An increasing number of instructive studies on experimental models and several genetic model systems of neuronal migration disorder have established the foundation of cortex formation and provided deeper insights into the genetic and molecular mechanisms underlying normal and abnormal neuronal migration.

Types and three-dimensional distribution of neuronal ectopias in the brain of mice prenatally subjected to X-irradiation.

The types and three-dimensional distribution of neocortical ectopias following prenatal exposure to X-irradiation were studied by a histological examination and computer reconstruction techniques. Pregnant ICR mice were subjected to X-irradiation at a dose of 1.5 Gy on embryonic day 13. The brains from 30-day-old mice were serially sectioned on the frontal plane at 15 microns, stained with HE and observed with a microscope. The image data for the sections were input to a computer, and then reconstructed to three-dimensional brain structures using the Magellan 3.6 program. Sectional images were then drawn on a computer display at 240 microns intervals, and the positions of the different types of neocortical ectopias were marked using color coding. Three types of neocortical ectopias were recognized in the irradiated brains. Neocortical Lay I ectopias were identified as small patches in the caudal occipital cortex, and were located more laterally in the neocortex in caudal sections than in the rostral sections. Periventricular ectopias were located more rostrally than Lay I ectopias, and were found from the most caudal extent of the presumed motor cortex to the most caudal extent of the lateral ventricle. Hippocampal ectopias appeared as continuous linear bands, and were frequently associated with the anterior parts of the periventricular ectopias.

Distribution of calbindin-D28K immunoreactive neurons in rat primary motor cortex.

Distribution of calbindin-D28K immunoreactive cells in the primary motor area of the adult rat neocortex was studied in the present experiment. In the primary motor cortex, calbindin-D28K immunoreactivity was found in two populations of cortical neurons. One was composed of neurons heavily labeled with anti-calbindin antibody, which were present in two bands corresponding to cortical layers II-III, and V. The morphological types of these cells were varied; they had oval, fusiform or mutiangular somata. The proximal dendrites of the heavily stained cells showed that these cells were non-pyramidal neurons, and they were either bitufted or multipolar cells. The other was a weakly stained population, mainly concentrated in layers II and III, that also contained pyramidal neurons. In addition, one outstanding feature of the neuropil staining deep to layer II was the labeling of the long, vertically oriented bundles of immunoreactive processes. Such a distinct pattern of calbindin-D28K immunoreactive neurons in the primary motor cortex suggests a relatively high density of calcium channels exists in the superficial layers of the rat primary motor cortex.

Changes in histological construction and decrease in 3H-QNB binding in the rat brain after prenatal X-irradiation.

To elucidate the mechanisms involved in deleterious neuronal and behavioral changes after prenatal ionizing irradiation, in vitro muscarinic acetylcholine (mACh) receptor binding and histological construction were investigated in 9-week old rat brains after 1.5 Gy X-ray exposure on embryonic day 15 (E15). A gross anatomical examination with a magnetic-resonance imaging system showed an irregular tissue construction in the hippocampus and cortex of the irradiated rat brain. Histological sections stained with hematoxylin and eosin also indicated that the structures of the hippocampus and cortex were obviously changed. In irradiated rats, the laminar structure of pyramidal cells was selectively deranged in the CA1 region. In vitro 3H-Quinuclidinyl benzilate binding in the hippocampus was significantly decreased (about 10%) in prenatal irradiated rats compared to that in sham-treated rats. On the other hand, no significant change in mACh receptor binding was observed in the cerebral cortex. The present study revealed that prenatal exposure to ionizing radiation may induce dysfunction of the cholinergic neuronal systems, especially in the hippocampus, resulting in deleterious changes in memory and behavior.